The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention.
Surgery, radiation therapy, and chemotherapy have been the standard accepted approaches for treatment of cancers including leukemia, solid tumors, and metastases. Immunotherapy (sometimes called biological therapy, biotherapy, or biological response modifier therapy), which uses the body's immune system, either directly or indirectly, to shrink or eradicate cancer has been studied for many years as an adjunct to conventional cancer therapy. It is believed that the human immune system is an untapped resource for cancer therapy and that effective treatment can be developed once the components of the immune system are properly harnessed. As key immunoregulatory molecules and signals of immunity are identified and prepared as therapeutic reagents, the clinical effectiveness of such reagents can be tested using well-known cancer models. Immunotherapeutic strategies include administration of vaccines, activated cells, antibodies, cytokines, chemokines, as well as small molecular inhibitors, anti-sense oligonucleotides, and gene therapy (Mocellin, et al., Cancer Immunol. & Immunother. (2002) 51: 583-595; Dy, et al., J. Clin. Oncol. (2002) 20: 2881-2894, 2002).
Cytokines are extracellular protein messenger molecules produced by cells involved in inflammation, immunity, differentiation, cell division, fibrosis, and repair (Smith, K. A.: Blood (1993) 81: 1414-1423). Cytokines such as such as TNFα, IL-1α, TGFβ, and CD40 ligand also function as cell surface signaling molecules. A characteristic of cytokines that distinguishes them from other natural bioactive molecules is that cytokines are generated in response to stimulation rather than being constitutively produced. Cytokine genes are highly inducible and their encoding mRNA levels subject to regulation by a transcriptional factors, such as NFκB, NF-AT, and AP-1 (Oppenheim, et al., “Introduction to the role of cytokines in innate host defense and adaptive immunity” In: Cytokine Reference (eds. Oppenhein and Feldmann. Pp 3-20, 2001)). Cytokine production generally lasts a few hours to a few days and has a short action radius. Thus, cytokines act mainly on neighboring cells rather then systemically. When administered systemically as a pharmaceutical, cytokines exhibit serious toxicity causing multiple symptoms including fever, hypotension, headache, malaise, and weakness. Toxicity makes is difficult to administer cytokines in clinically relevant dosages.
The first cytokine to obtain approval for cancer therapy is Interleukin-2 (IL-2) (Rao, et al, Annual Rev. Immunol. (1997) 15: 707-747). The primary role of IL-2 is to stimulate the growth and proliferation of T lymphocytes, however, it has stimulatory effects on a variety of other immune cells including natural killer (NK) cells, lymphokine-activated killer (LAK) cells, monocytes, and macrophages (Id.). While IL-2 has shown some promise in the treatment of renal cancer and melanomas (Silagi, et al., J. Biol. Response Modifiers. (1986) 5: 411-422), it has serious side affects including damage to the blood vessels of the body (capillary leak syndrome) that limit is usefulness for other cancers. Intratumoral administration of IL-2 is somewhat more effective than systemic administration (Silagi, et al., J. Biol. Response Modifiers. (1986) 5: 411-422; Sone, et al., Oncology (1994) 51: 170-176), however, intratumoral administration is not feasible for disseminated disease.
The concept of adoptive cellular therapy for tumors, first presented nearly 50 years ago by Mitchison (Mitchison, N. A.: J Exp Med. (1955) 102:157-77), has at its goal the elimination of cancer through the transfer of activated T-cells and/or natural killer cells. Adoptive immunotherapy is based on the belief that tumor specific cytotoxic T-cells are present in cancer patients, but that such cells have not been primed and/or that the in vivo function of the cells is impaired. To prime the cells, peripheral T-cells are removed from the patient, activated ex vivo, and then re-infused. The step of ex vivo activation also may include exposure to the patient's tumor cells or to a tumor cell vaccine. Although T-cell based adoptive immunotherapy provides a potentially promising form of cancer treatment, it has failed to induce a long-lasting response in the majority of patients who have received this therapy (Lum, et al., J Immunother. (2001) 24:408-19).
Although much has been learned about controlling and directing an immune response, there is need for newer and more effective immunotherapeutic approaches to cancer therapy.